A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects

Abstract

Aim: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers.

Methods: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 μg·kg(-1)·min(-1), each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate.

Results: Peak concentrations (C(max)) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107-0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng·h·mL(-1) (range, 3.2-6.8 ng·h·mL(-1)). The volume of distribution (V) was 48 L (range, 30.8-80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%-12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E(0), E(max), and EC(50) were 68 bpm, 73 bpm and 8.1 μg/L, respectively.

Conclusion: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine.

Figure 1

Chemical structure of higenamine.

Figure 2

Dose regimen chart. Higenamine was intravenously infused at escalating doses, each of which was given for 3 min.

Figure 3

The average concentration-time curve of higenamine in the plasma and the heart rate-time curve from healthy Chinese subjects after intravenous administration of 22.5 μg/kg (n=10) higenamine hydrochloride (mean±SD).

Figure 4

Observed data values (DV) vs population predicted data (PRED). (A) Individual predicted data (IPRED) and (B) Conditional Weighted Residual (CWRES) vs (C) population predicted data (PRED) and (D) Visual Predictive Check (VPC) profile of plasma concentration.

Figure 5

Observed data values (DV) vs population predicted data (PRED). (A) Individual predicted data (IPRED) and (B) Conditional Weighted Residual (CWRES) vs (C) population predicted data (PRED) and (D) Visual Predictive Check (VPC) profile of heart rate.